Worldwide, lung cancer, particularly K-ras mutant lung cancer, is still the leading cause of cancer mortality because of a high incidence, and a low cure rate. Unfortunately, pharmacologic attempts directly targeting K- ras have thus far failed, clearly indicating that there is an urgent need for novel approaches to bring clinical benefits to patients with this undruggable molecular profile. We recently made an astonishing sex-specific discovery using a mouse model for K-ras-driven lung cancer (CC-LR). We found that deletion of STAT3 in K- ras mutant lung epithelial cells significantly inhibited lung cancer development in female mice but, surprisingly, caused a dramatic enhancement of lung tumorigenesis in male mice. This sex-dependent tumor disparity was accompanied by significant changes of NF-?B regulated target genes and inflammatory response in the lung tumor microenvironment which was regulated by estrogen receptor (ER) signaling. In humans, the risk and outcome of lung cancer are also vastly distinct between men and women, especially for smokers. However, the reason for this sex disparity is poorly understood and extremely underappreciated. It is known that estrogen could have anti-inflammatory effects. However, the interplay between estrogen/ER signaling, and STAT3/NF- ?B mediated cytokine network in shaping the lung microenvironment and promotion of lung cancer is unknown. Our novel finding that the crosstalk between STAT3 and ER signaling is an essential regulator of NF-?B mediated cytokine response in K-ras mutant lung tumors provides us with a direct molecular insight into these sex differences. It will facilitate identification of the signaling pathways that lung cancer cells use to recruit and reprogram myeloid cells, thus providing new pathways to intercept for preventive and therapeutic purposes. Accordingly, our goals for this project are to determine the sex and cell type specific mechanistic roles of specific inflammatory signaling cues and functional preventive and therapeutic significance of targeting these inflammatory pathways in the pathogenesis of K-ras mutant lung cancer. Three specific aims are proposed to achieve these goals: (Aim 1) To dissect the sex-specific interplay between STAT3/NF-?B mediated cytokine network and estrogen receptor signaling in K-ras mutant lung tumorigenesis. (Aim 2) To investigate the chemopreventive and therapeutic effects of targeting the IL-6/STAT3 pathway in K-ras mutant lung cancer. (Aim 3) To analyze sex- and cell type-specific global expression programs downstream of mutant K-ras in lung cancer. We expect our study will elucidate sex- and cell-type specific mechanisms that will be fundamental in delineating targets for tailoring rationally directed sex-oriented personalized preventive and therapeutic strategies to overcome K-ras mutant lung tumors. It could also help us to improve the efficacy of currently available immunotherapy regimens, to develop a panel of unique and sex specific clinical predictive and prognostic biomarkers to identify responders and non-responders, and to explore mechanisms of susceptibility or resistance to therapy in these patients.